Old Drugs, New Tricks

In recent years two Scandinavian studies have shown that fibrates (lipid-lowering drugs) reduce atheroma plaque formation , through an unknown mechanism. Bart Staels and Professor Jean-Charles Fruchart (INSERM 325, Lille 2 University and Lille Pasteur Institute), in collaboration with the teams headed by Jacques Maclouf (INSERM 348, directed by Sylviane Levy-Toledano) and Alain Tedgui (INSERM 141, directed by Bernard Levy), have now discovered why : fibrates have an anti-inflammatory effect on vessel walls.

Fibrates, a class of drugs that reduce blood fat levels, have been used for about a decade in the treatment of some forms of hyperlipidemia and atherosclerosis. Fibrates bind to PPARa, a receptor present in the liver and involved in fatty acid breakdown . PPARa acts as a messenger, allowing the body to adapt to its nutritional environment (especially ingestion of large amounts of fat). Fibrates, synthetic compounds that bind to this receptor, stimulate PPARa activity and thereby reinforce its lipid-lowering action.

The INSERM researchers showed that PPARa receptors are also present in vascular muscle cells, which participate in the formation of atheroma plaque and restenosis after angioplasty . These vascular PPARa receptors were found to inhibit the inflammatory response of the vascular wall which leads to atheroma plaque formation (see inset). Fibrates, by activating PPARa, inhibit the production of inflammatory cytokines such as interleukin-6 (IL-6) and prostaglandin by vascular muscle cells in vitro. They also inhibit the induction of an enzyme called Cox-2 (cyclooxygenase), which serves as a marker of vascular cell inflammation.

The mechanism of action of these PPARa receptors in the vascular wall was also elucidated. The receptors exert at least part of their anti-inflammatory effect by interfering with a signaling pathway called NFkB, which is also activated during inflammatory cytokine production. PPARa inhibits the inflammatory response by

Contact: Jean-Charles Fruchart
33 3 20 87 73 52
French National Institute for Health and Medical Research (INSERM)

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